Lecture 13 - CNS Toxicants II - Part 2 Flashcards
List the Methylxanthines.
Caffeine
Theobromine
Theophylline
What are the sources of Theobromine?
Cocoa beans, chocolate, cocoa bean shells and mulch
Theobromine poisoning is most common in?
Dogs
When does risk of Theobromine increase?
during holidays
associated with eating candy
Most Theobromine poisonings occur from ingestion of?
milk chocolate
The most dangerous chocolate an animal can consume is?
Baker’s chocolate
Cocoa bean ____ or _____ used as bedding
cause toxicosis in horses.
hulls, waste
List the sources of Caffeine
- Coffee, tea, chocolate, soft drinks, some human and veterinary medications
Most caffeine poisoning results from?
caffeine tablet ingestion especially by dogs
Theophylline can be found in?
Tea and medications for asthma (bronchodilators),
e.g., aminophylline (= theophylline + ethylene
diamine)
List the risk factors of Theobromine toxicosis.
1. Which species are susceptible? Which, out of these, are the MOST susceptible?
2. What is the half-life of Theobromine in the most susceptible species?
3. The use of ~this~ Theobromine containing ingredient is illegal in race horses.
Susceptible species: all
* Dogs are more susceptible because of
– Their eating habits
– t½ of theobromine is long in dogs (17.5h
compared to 2-3h in humans)
* Illegal use of caffeine to hype race-horses
Describe Caffeine’s ADME
* Caffeine: readily absorbed after ____ exposure with peak serum levels in 30-60 min (t½ = 4.5h)
* Crosses the _____, ______ and ________ gland
* Metabolism occurs in the ____ by microsomal enzymes (?)
* Eliminated through ___ and ____
* It undergoes significant ________ recirculation
– Metabolites excreted via bile are reconverted to __________ in the intestine and ________
- Caffeine: readily absorbed after oral exposure with peak serum levels in 30-60 min (t½ = 4.5h)
- Crosses the BBB, placenta and mammary gland
- Metabolism occurs in the liver by microsomal enzymes (demethylation & phase II conjugation)
- Eliminated through urine and bile
- It undergoes significant enterohepatic recirculation
– Metabolites excreted via bile are reconverted to methylxanthines in the intestine and reabsorbed
Describe Theobromine’s ADME.
Theobromine is absorbed more ______ than
caffeine, plasma levels peak in 10h
– Like caffeine it is metabolized in the _____
* Excretion is slow in ____ (t½ = 17.5h)
Theobromine: absorbed more slowly than
caffeine, plasma levels peak in 10h
– Like caffeine it is metabolized in the liver
* Excretion is slow in dogs (t½ = 17.5h)
Describe Theophylline’s ADME.
Theophylline: _____ absorption with plasma
peak levels in 1.5h
– Metabolized in the ______ with elimination t½ = 5- 8h in dogs and cats
* Sustained release products are absorbed more _____ (peak plasma concentration in 16h)
Theophylline: rapid absorption with plasma
peak levels in 1.5h
– Metabolized in the liver with elimination t½ = 5- 8h in dogs and cats
* Sustained release products are absorbed more slowly (peak plasma concentration in 16h)
MX induce their toxic effects through various mechanisms. A definitive mechanism of action has ____ been identified, but clinical signs in animals are believed to be related to __________ inhibition of cellular ________ receptors.
Adenosine acts as an __________ and Regulator of _______ rhythm.
Competitive inhibition of cellular adenosine receptors, results in (3?).
Methylxanthines also increase intracellular __________ levels by increasing cellular _______ entry and inhibiting intracellular sequestration of ________ by the sarcoplasmic reticulum of _______ muscle. The net effect is increased ______ and ________ of skeletal and cardiac muscle.
Methylxanthines act through inhibition of cellular _________, increasing intra-cellular _______, which regulates many cellular
activities including ___ channels, adrenaline, glucagon, etc. However, levels of
methylxanthines capable of inhibiting phoshodiesterase in vivo can only be
achieved after massive __________.
Other mechanism of actions may include cellular calcium reuptake inhibition
and competition for benzodiazepine receptors in the brain causing opposite
effects to benzodiazepines.
Stimulation of sympathetic nervous system : Increases levels of circulating
epinephrine and norepinephrine
MX induce their toxic effects through various mechanisms. A definitive mechanism of action has not been identified, but clinical signs in animals are believed to be related to competitive inhibition of cellular adenosine receptors.
Adenosine acts as Anticonvulsant and Regulator of cardiac rhythm. Competitive inhibition of cellular adenosine receptors, results in CNS stimulation, diuresis, and tachycardia.
Methylxanthines also increase intracellular calcium levels by increasing cellular calcium entry and inhibiting intracellular sequestration of calcium by the sarcoplasmic reticulum of striated muscle. The net effect is increased strength and contractility of skeletal and cardiac muscle.
Methylxanthines act through inhibition of cellular phosphodiesterase, increasing intra-cellular cyclic AMP. Cyclic AMP regulates many cellular activities including K+ channels, adrenaline, glucagon, etc. However, levels of
methylxanthines capable of inhibiting phoshodiesterase in vivo can only be
achieved after massive overdose. Other mechanism of actions may include cellular calcium reuptake inhibition and competition for benzodiazepine receptors in the brain causing opposite effects to benzodiazepines.
Stimulation of sympathetic nervous system : Increases levels of circulating
epinephrine and norepinephrine
Clinical signs of Caffeine toxicosis include?
- Signs in 1-2h
- Agitation, hyperactivity, tremors and seizures, abnormal behavior, panting, tachycardia, weakness, ataxia, clonic convulsions,
vomiting, diarrhea, diuresis, dehydration, hypokalemia, hyperthermia, hypertension,
cyanosis, coma and death from cardiac arrhythmias or respiratory failure - Bouncing effect when a standing dog is lifted a few inches off the floor and dropped
What are the clinical signs of Theobromine toxicosis?
- Signs occur in 2-4h
- CNS excitation with restlessness, tremors, seizures, ataxia and hyperthermia
- Panting, polyuria, polydipsia, vomiting, diarrhea and dehydration
- Cardiac arrhythmias (tachycardia, premature ventricular contraction, bradycardia)
- Weakness, coma and death from cardiac or respiratory failure
List the clinical signs of Theophylline toxicosis
- Nausea, vomiting and abdominal pain
- Hypotension and cardiac arrhythmias
- Muscle tremors and weakness
- Agitation, seizures, hyperactivity and behavioral abnormalities
How do you Dx Methylxanthine toxicosis ?
- History of exposure
- Clinical signs
- Measurement of methylxanthines and their metabolites concentrations:
– Stomach contents, plasma/serum, urine or liver can be used
What are the DDx for Caffeine toxicosis?
- Conditions that cause acute onset of CNS and cardiac signs
– Strychnine, nicotine, amphetamine, cocaine
– Organochlorine insecticides
– Organophosphates and carbamates
– Metaldehyde
– Tremorgenic mycotoxicosis
– Fluoroacetate
– Cardiac glycosides
How do you Tx Methylxanthine toxicosis?
- No antidote. Decontaminate:
– Emesis (apomorphine/H2O2), gastric lavage, activated charcoal (repeated doses for high
exposures) - Provide basic life support
– Relieve respiratory difficulties: maintain airway patency and give artificial respiration
– Give IV fluids - To maintain renal perfusion, increase methylxathines excretion, and correct electrolyte imbalances
How can you use symptomatic therapy to Tx?
- Symptomatic therapy
– Diazepam or midazolam for seizures/
hyperactivity. Use a barbiturate or other
general anesthetic for seizures unresponsive
to diazepam
– Methocarbamol or diazepam for tremors
– Relieve cardiac dysfunction: - Atropine for bradycardia, propranolol for
tachycardia, metoprolol for tachyarrhythmias,
lidocaine for premature ventricular contractions
What plant is pictured below? List its scientific name and alternative/common names
List its habitat and where it is commonly found geographically.
Water Hemlock (Cicuta) (Cowbane, beaver poison, poison parsnip)
* Native bi/perennial herb (4-5ft)
* Habitat: swamps, marshes, along
streams, meadows, irrigation ditches
* Among the most violently toxic plants known
* Found thro’ out US
Often confused with poison hemlock, which is nicotinic.
What plant is pictured below? List its scientific name and alternative/common names
List its habitat and where it is commonly found geographically.
Bracken Fern
* Native perennial herb;
occurs throughout US
Toxic principles:
* Thiaminase
* Ptaquiloside
* Cyanogenic glycoside
* Bone marrow factor
* Contaminates hay
Describe the Bracken Fern MOT
Thiamine is required for the proper function of __________ _________ which is the enzyme that links Gylcolysis with Krebs cycle.
It is also required for the proper function of ________ __________ ___________ which is also a key enzyme of the ____ cycle.
Without sufficient amounts of Thiamine there will be impaired conversion of _______ to ______ _____ as well as impaired oxidation of _______ _______ to ________ _______.
This can result in CNS _____ through several mechanisms:
1) through impaired or reduced production of ___
2) Due to impaired production of _______ and ______, because this requires acetyl CoA
3) Disruption of several Amino acid neurotransmitters that are dependent on
________ _______, and include Glutamate, GABA, Aspartate
This diagram highlights the significance of thiamine in CHO metabolism and the consequences of its deficiency.
Thiamine is required for the proper function of Pyruvate dehydrogenase which is the enzyme that links Gylcolysis with Kreb cycle.
It is also required for the proper function of alpha ketoglutarate dehydrogenase which is also a key enzyme of Kreb cycle.
Without sufficient amounts of Thiamine there will be impaired conversion of
Pyruvate to Acetyl CoA as well as impaired oxidation of alpha ketoglutarate to succinyl CoA.
This can result in CNS dearrangement through several mechanisms
1) through impaired or reduced production of ATP
2) Due to impaired production of Acetylcholine and myelin, because this
requires acetyl CoA
3) Disruption of several Amino acid neurotransmitters that are dependent on
alpha ketoglutarate, and include Glutamate, GABA, Aspartate
see below
Following exposure the degree of absorption depends on animal spp, in
Ruminants its low, 25 % and in monogastrics its as high as 95%.
P-glycoproteins are efflux pumps (efflux transporters) in some tissues (e.g., the
blood-brain barrier, intestine and liver) that pump out toxicants as they enter
the cell.
So, they act much the same as bouncers at a nightclub who make sure that bad
individuals stay out of the club, hence the name “cellular bouncers”.
In pharmacology, they are responsible for development of drug resistance.
Describe the MOT of Marijuana toxicosis.
What plant is pictured below?
List its habitat and where it is found geographically.
White Snakeroot
(
Eupatorium rugosum)
* Perennial plant, grows in
eastern North America
westward to MN & TX
* Toxic principle: tremetone
* Susceptible species: all
– Cattle, equine, sheep,
goats, dog, cat
Most problems occur in OH, IN, IL, NC & MO
